Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Abstract

Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface‐to‐volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+‐induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5‐trisphosphate (IP3) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage‐gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.

Astrocyte as Spatiotemporal Integrating Detector of Neuronal Activity

“…The functional role of astrocyte calcium signaling remains intensely debated. One of the principal reasons for such a debate is that the astrocytic Ca 2+ dynamics possesses high complexity which was confirmed by new experimental approaches to study the signaling of astrocytes at qualitatively new spatial-temporal resolutions (Volterra et al, 2014; Bindocci et al, 2017; Wu et al, 2018). Another reason was the evidence of bi-directional astrocytic regulation of neuronal activity referred as gliotransmission [Ca 2+ -dependent release of neurotransmitters (glutamate, D-serine, ATP) by astrocytes] (Araque et al, 2014; Bazargani and Attwell, 2016; Fiacco and McCarthy, 2018; Savtchouk and Volterra, 2018).…”

The Role of Astrocytes in the Central Nervous System Focused on BK Channel and Heme Oxygenase Metabolites: A Review

“…Astrocytic depolarization by high extracellular K + increased the frequency of Ca 2+ events through activation of VGCC in cultured astrocytes [48]. In this study, the morphological and structural plasticity of astrocytic processes could be translated into the frequency of spontaneous Ca 2+ signaling [48]. Taken together, adult astrocytic Ca 2+ can be elevated by ionic influx from extracellular space and can influence astrocytic morphological plasticity, mitochondria biogenesis, and LPS-mediated reactivity.…”

“…Interestingly, diminished extracellular Ca 2+ concentration markedly and reversibly abolished spontaneous signals, while IP 3 R2 KO mice also exhibited spontaneous and compartmentalized signals, suggesting that the adult mouse brain also uses extracellular Ca 2+ for neurovascular coupling [47]. Astrocytic depolarization by high extracellular K + increased the frequency of Ca 2+ events through activation of VGCC in cultured astrocytes [48]. In this study, the morphological and structural plasticity of astrocytic processes could be translated into the frequency of spontaneous Ca 2+ signaling [48].…”

Spontaneous Ca2+ Fluctuations Arise in Thin Astrocytic Processes With Real 3D Geometry

“…Therefore, we can only speculate about how these spontaneous Ca 2+ events, triggered by Ca 2+ entry through NCX can propagate into astrocytic branchlets and can be amplified and propagated as a result of various downstream mechanisms, including Ca 2+ -dependent Ca 2+ release in association with activation of inositol 1,4,5-trisphosphate receptors (IP 3 R) or mitochondrial permeability transition pores (Semyanov et al, 2020). It was experimentally observed, however, that the appearance and frequency of slower spontaneous Ca 2+ events in somewhat larger astrocytic processes (characterized by SVR < 3) depend on SVR (Wu et al, 2019). Also, compartmentalized Ca 2+ waves as predicted by the dynamically rich repertoire of distinct Ca 2+ -dependent Ca 2+ release dynamics (Matrosov et al, 2019) may travel and act by modulating local spontaneous Ca 2+ fluctuations.…”